Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics

Definitions

• the invention relates to tertiary amides 4-Amino-2-ureido-pyrimidine-5-carboxylic acid and its acid addition salts.
• the invention relates to substituted 4-amino-2- (imidazolin-2-one-1-yl) pyrimidine-5-carboxylic acid [N- (fluoroalkoxy-substituted) phenylamides] and their acid addition salts.
• the object of the invention was to provide connections places that are well tolerated, a therapeutically usable Develop hypolipidemic effects.
• the task is to find connections in which in addition to sufficient hypolidemic effect the cytotoxic properties in the Comparison to those described in European Patent 0 557 879 Connections only to a greatly reduced degree or no longer at all are watching.
• the invention further relates to 2 processes for the preparation of 4-amido-2-ureido-pyrimidine-5-carboxamides of formula I.
• Process A for the preparation of the compounds of the formula I characterized in that a compound of the formula II after in situ activation (conversion into the corresponding acid chloride, for example with thionyl chloride), with a compound of the formula III in which R 1 , R 2 and R 3 have the meaning given for formula I, at a temperature of 0 ° C. to 200 ° C. in a suitable solvent (such as DME) with or without the addition of an auxiliary base (such as NEt 3 ) converted to a compound of formula I, and the resulting compound of formula I optionally converted into a physiologically acceptable salt or an obtained salt optionally converted into a physiologically acceptable salt.
• a suitable solvent such as DME
• an auxiliary base such as NEt 3
• Process B for the preparation of the compounds of the formula I characterized in that a compound of the formula IV in which R 1 , R 2 and R 3 have the meanings given for the formula I is cyclized to a compound of the formula I.
• the preparation of the compounds of type IV, as well as the cyclization to give compounds of type I, are described in EP-0 557 879.
• the 4-amino-2- (4,4-dimethyl-imidazolin-2-one-1yl) pyrimidine-5-carboxylic acid alkyl ester by known methods for 4-amino-2- (4,4-dimethyl-imidazolin-2-one-1-yl) pyrimidine-5-carboxylic acid saponified.
• the present invention also relates to pharmaceutical preparations which in addition to non-toxic, inert, pharmaceutically suitable carriers or contain several active substances according to the invention or which consist of one or several active substances according to the invention and methods for Manufacture of these preparations.
• non-toxic, inert, pharmaceutically suitable carriers pharmaceutically acceptable solid, semi-solid or liquid diluents
• Understand fillers and formulation auxiliaries of all types which according to the Mix with the active ingredient in a suitable for administration Bring shape.
• suitable forms of use of the compounds according to the invention come for example tablets, coated tablets, capsules, pills, aqueous solutions, Suspensions and emulsions, possibly sterile injectable solutions, non-aqueous Emulsions, suspensions and solutions, sprays and preparation forms with protracted release of active substance into consideration.
• the therapeutically active compounds are listed in the above pharmaceutical preparations expedient in a concentration of about 0.1, preferably from 0.5 to 99.0, preferably to 70.0 percent by weight of the total mixture.
• the application concentrations for solutions and aerosols in the form of Spray is generally 0.1 to 20, preferably 0.5 to 5 Percent by weight.
• compositions listed above can in addition to Active substances according to the invention also other pharmaceutical active substances contain.
• the pharmaceutical preparations listed above are produced in the usual way by known methods, e.g. B. by mixing the or Active substances (s) with the carrier (s).
• the active ingredients or the pharmaceutical preparations can be administered orally, parenterally, intraperitoneally and / or rectally.
• the z. B. usable as hypolipidemics compounds of the present Invention, and its salts, can be used in the manufacture of pharmaceutical Preparations which contain an effective amount of the active substance contain together with carriers and which are enteral and parenteral administration.
• Tablets are preferably used or capsules (gelatin capsules), which contain the active ingredient together with Diluents or carriers, e.g. B. lactose, dextrose, cane sugar, Mannitol, sorbitol, cellulose, various types of starch and / or glycine, and Lubricants such as silica, talc, stearic acid or their salts, such as Contain magnesium or calcium stearate, and / or polyethylene glycol.
• Diluents or carriers e.g. B. lactose, dextrose, cane sugar, Mannitol, sorbitol, cellulose, various types of starch and / or glycine, and Lubricants such as silic
• Tablets also contain binders such as magnesium carbonate, Magnesium aluminum silicate, starch, gelatin, traganath, methyl cellulose, Sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone and, if required Colorants, flavors and sweeteners.
• binders such as magnesium carbonate, Magnesium aluminum silicate, starch, gelatin, traganath, methyl cellulose, Sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone and, if required Colorants, flavors and sweeteners.
• injectable solutions preferably isotonic aqueous solutions or suspensions that are sterilized can be and auxiliaries, such as preservatives, stabilizers, wetting agents and / or Emulsifiers, solubilizers, salts for regulating the osmotic May contain pressure and / or buffer substances.
• the invention pharmaceutical preparations which, if desired, further pharmacologically can contain effective substances, z. B
• Oral use is in standard pharmaceutical preparations, for example in the form of tablets, dragees or capsules, e.g. B. pro Daily dose 5 to 1000 mg, preferably 20 to 200 mg, of the active ingredient in Mixture with a common carrier and / or constituent contain, with single doses of 5 to 200 mg, preferably one to three times daily, can be given.
• Dosage and type of application of the active ingredients can be done by any specialist easy to do due to his expertise.
• the compounds of formula I and their physiologically tolerable salts Due to their low cytotoxicity, they are ideal drugs for the treatment of Lipid metabolism disorders, especially hyperlipidemia Compounds are particularly suitable by stimulating the LDL receptor, to effectively lower plasma levels.
• the following findings support the pharmacological activity of the compounds described.
• the preparation of the mRNA was carried out according to the method of Chomczynski, P. and Sacchi, N., Anal. Biochem. 162, 156-159 (1987).
• organs such as liver
• the frozen tissue was previously dry-homogenized in a mortar and the mRNA further enriched using oligo dT using standard methods (see Sambrook, J., Fritsch, EF and Maniatis, T., Molecular Cloning, second edition, Cold Spring Harbor (1989); this collection of methods also contains descriptions of all other relevant standard molecular biological methods used here).
• 5 to 20 ⁇ m of the dissolved mRNA obtained in this way were denatured using standard methods and separated on 1% horizontal agarose gels.
• the mRNA was transferred to Hybond N membranes (Amersham) by capillary blot.
• a partial LDL receptor cDNA clone was used as the specific hybridization sample and a plasmid containing a ⁇ -actin gene as the internal standard. Both plasmids were labeled with a random primer kit from Amersham up to a specific activity of 5 x 10 9 cpm / ⁇ g.
• Prehybridization, hybridization and washing of the filters were carried out according to standard procedures.
• the filters were then exposed to Cronex 4 films (Dupont) overnight for up to 14 days in the presence of an intensifying screen at -70 ° C. and the hybridization signals were quantified using the film density using a commercially available laser densiometer. The quotient of the intensity of the LDL receptor band and the actin band was then determined as an internal standard for correcting yield variations.
• Table I shows stimulation of LDL receptor mRNA expression in Rat liver 6 hours after application of selected compounds of the Formula I (dose of 30 mg / kg). Liver tissue was removed and in liquid nitrogen snap frozen.
• the mRNA was then isolated as described and by means of the Northern blot technique determined the relative LDL receptor mRNA levels.
• tumor cells bronchial carcinoma cells, A549, colon carcinoma cells, HT29, renal carcinoma cells, hela cells
• bronchial carcinoma cells A549, colon carcinoma cells, HT29, renal carcinoma cells, hela cells
• the incubation with test substance concentration series takes place for 72 hours at 37 ° C., 5% CO 2 , 95% rel. Humidity.
• Each compound concentration or control is tested in four parallel incubations.
• 50 ⁇ l of MTT [3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide] in 2.5 mg / ml PBS are added.
• MTT is reduced to a red insoluble dye.
• the supernatant is removed after a further 7 to 24 hours of incubation.
• the resulting insoluble dye is dissolved in 100 .mu.l DMSO with gentle shaking and the absorbance is measured in a Multiscan Photometer 340 CC from Flow at 492 nm.
• the results are calculated as quotients from the average absorbance values of the test substances and the control values.
• the fluctuations of the individual determination values within the parallel values are less than 15%.
• the IC 50 value for the specified compounds is read from dose-response diagrams.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Obesity (AREA)
• Diabetes (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Hematology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicinal Preparation (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1996
  • 1996-06-24 DE DE19625089A patent/DE19625089A1/de not_active Withdrawn
• 1997
  • 1997-06-04 US US08/868,991 patent/US5939424A/en not_active Expired - Lifetime
  • 1997-06-12 DK DK97109547T patent/DK0816358T3/da active
  • 1997-06-12 AT AT97109547T patent/ATE281452T1/de active
  • 1997-06-12 DE DE59712053T patent/DE59712053D1/de not_active Expired - Lifetime
  • 1997-06-12 EP EP97109547A patent/EP0816358B1/fr not_active Expired - Lifetime
  • 1997-06-12 PT PT97109547T patent/PT816358E/pt unknown
  • 1997-06-12 ES ES97109547T patent/ES2230575T3/es not_active Expired - Lifetime
  • 1997-06-23 CA CA002208630A patent/CA2208630C/fr not_active Expired - Fee Related
  • 1997-06-23 MX MX9704704A patent/MX9704704A/es active IP Right Grant
  • 1997-06-23 NO NO19972943A patent/NO312414B1/no not_active IP Right Cessation
  • 1997-06-23 JP JP16581597A patent/JP4101906B2/ja not_active Expired - Fee Related

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